Novel Targets in Endocrine Responsiveness. While Project 1 takes a focused analysis of specific signaling around cellular stress and cell fate decisions. Project 2 will take a functional genomics approach and study cell cycle progression in endocrine sensifive and resistant cells. Drs. Weiner and Golemis will lead the team in Project 2 and apply a powerful synthetic lethal screen approach that we have previously used to study EGFR-mediated signaling. Using a focused siRNA library targeting known ER-driven genes implicated in endocrine responsiveness, we will determine which genes, when their expression is inhibited, affect the ability of E2, TAM, and ICI to regulate cell cycle progression. Importanfiy. the siRNA library will be applied to the same cell models used in Proiect 1. The team will validate candidate genes that primarily affect cell proliferation {i.e., cell cycle), whereas candidate genes associated with specific cellular stress pathways and cell survival {e.g., apoptosis, autophagy, necrosis) will be studied in Project 1.